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WO2017189866A1 - Analogues de la polymyxine utiles en tant que potentialisateurs d'antibiotique - Google Patents

Analogues de la polymyxine utiles en tant que potentialisateurs d'antibiotique Download PDF

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WO2017189866A1
WO2017189866A1 PCT/US2017/029879 US2017029879W WO2017189866A1 WO 2017189866 A1 WO2017189866 A1 WO 2017189866A1 US 2017029879 W US2017029879 W US 2017029879W WO 2017189866 A1 WO2017189866 A1 WO 2017189866A1
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group
compound
oxo
hydroxy
mmol
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Troy LISTER
Rajiv Sharma
Thomas ZABAWA
Robert Zahler
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Spero Opco
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Spero Opco
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
    • C07K7/62—Polymyxins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure provides polymyxin analogues useful for treating bacterial infections and/or useful for sensitizing bacteria, including Gram negative bactena, to the effects of other antibacterial agents and thereby increasing the efficacy of the other antibacterial agents.
  • Gram-negative bacteria cause more than 40% of all septicemic infections and many of the Gram-negative bacteria are resistant to multiple antibiotics.
  • Gram-negative bacteria possess iipopolysaceharide as a component of the outer membrane, which inhibits die diffusion of many antibacterial agents deeper into the cell, where their ultimate targets are located.
  • Many antibacterial agents effective against Gram-positive bacteria lack activity against Gram-negative bacteria.
  • Polymyxins are a group of closely related antibiotic substances produced by strains of Paenibacillus polymyxa and related organisms. These cationtc drugs are rela tively simple peptides with molecular weights of about 1000.
  • Polymyxins, such as polymyxin B, are decapeptide antibiotics, i.e., they are made often (10) aminoacyl residues. They are bactericidal and especially effective against Gram- negative bacteria such as Escherichia coli and other species oi Enterobacteriaceae, Pse domonas.
  • Acinetobacter baurtiannii and others.
  • polymyxins have severe adverse effects, including nephrotoxicity and neurotoxicity. These drugs thus have limited use as therapeutic agents because of high systemic toxicity.
  • R 1 and R 2 carry the following definitions:
  • R 1 is selected from hydrogen and optionally substituted Ci- C4 alkyl.
  • R 2 is selected from -C(0)-heterocyclyl, -heterocyclyl, and -C(0)-aryl, each of which is optionally substituted; or R 2 is selected from -C(0)NH-N(R 4 )-C(0)R 6 and -W-X-Y.
  • R 1 and R 2 are taken together to form an optionally substituted oxo-substituted heterocyclyl.
  • W is selected from C(O), CH 2 , P(0)(OH), and S(0) 2 .
  • X is selected from CH(R 3 ) and optionally substituted phen-l,2-diyl, wherein R 3 is selected from -CH(OH)CH 3 , -CH(CH 3 ) 2 and -heterocyclyl.
  • R 4 is selected independently selected at each occurrence from hydrogen and optionally substituted C1-C4 alkyl and R 5 is selected from C1-C4 alkyl, heterocyclyl and cycloalkyl, wherein R 5 is optionally substituted; or R 4 and R 5 bound to the same nitrogen atom may be taken together to form an optionally substituted heterocyclyl group.
  • R 6 is selected from C1-C4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, -NH(Ci-C 4 alkyl), N(Ci-C 4 alkyl)2, heterocyclyl and cycloalkyl, wherein R 6 is optionally substituted.
  • R 7 is selected from hydrogen, -OH, and optionally substituted C1-C4 alkyl.
  • the dashed line (— ) in formula I represents a stereospecific bond selected from (R) and (S).
  • R 1 is hydrogen
  • W is C(O)
  • X is -CH(OH)CH 3
  • Y is -NHC(0)R 6
  • R 6 is other than methyl, 2-aminocyclopentyl, cyclohexylhydroxymethyl, 1- cyclohexyl-l-aminoethan-2-yl, or 5-(sec-butyl)-piperidin-3-yl.
  • compositions comprising a compound of formula I together with a pharmaceutically acceptable carrier.
  • the disclosure includes a method for treating a bacterial infection in a patient, comprising administering a therapeutically effective amount of compound of formula I to the patient.
  • the compound of formula I may be administered as the only active agent or administered in combination with one or more additional active agents.
  • the disclosure also includes a method of sensitizing bacteria to an antibacterial agent, comprising administering to the patient, simultaneously or sequentially, a therapeutically effective amount of the antibacterial agent and a compound of formula I.
  • Formula I encompasses all compounds that satisfy formula I, including any enantiomers, racemates, stereoisomers, tautomers, as well as all pharmaceutically acceptable salts, of such compounds.
  • "Formula I” includes all subgeneric groups of formula I unless clearly contraindicated by the context in which this phrase is used.
  • Compounds of formula I include all compounds of formula I having isotopic substitutions at any position.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include n C, 1 C, and 14 C.
  • the disclosure includes embodiments in which any one or more hydrogen atoms are replaced with deuterium atoms.
  • an "active agent” means a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the subject.
  • the indirect physiological effect may occur via a metabolite or other indirect mechanism.
  • the "active agent” may also potentiate, or make more active another active agent.
  • the compounds of formula I and II potentiate the activity of other antibacterial compounds when given in combination with another antibacterial compound, for example by lowering the MIC of the other antibacterial compound.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(0)NH2 is attached through carbon of the keto C(O) group.
  • An "aliphatic group” is a hydrocarbon group having the indicated number of carbon atoms in which the carbon atoms are covalently bound in single, double or triple covalent bonds in straight chains, branched chains, or non-aromatic rings. Aliphatic groups may be substituted.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 8 carbon atoms.
  • Ci-Ce-alkyl indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Other embodiments include alkyl groups having from 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. Ci-Cs-alkyl, Ci-C/ralkyl, and Ci-C2-alkyl.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.
  • alkenyl is a branched or straight chain aliphatic hydrocarbon group having one or more double carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms.
  • alkenyl include, but are not limited to, ethenyl and propenyl.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more triple carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms.
  • alkynyl include, but are not limited to, ethynyl and propynyl.
  • Alkoxy is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-0-).
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy,
  • Alkylthio indicates an alkyl group as defined above attached through a sulfur linkage, i.e. a group of the formula alkyl-S-. Examples include ethylthio and pentylthio.
  • Alkanoyl is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes through a carbonyl C(O) bridge.
  • the carbonyl carbon is included in the number of carbons, that is C2alkanoyl is a C]3 ⁇ 4C(C))- group.
  • Alkylester is an alkyl group as defined herein covalently bound to the group it substitutes by an ester linkage.
  • the ester linkage may be in either orientation, e.g., a group of the formula -OC(0)-alkyl or a group of the formula -C(0)0-alkyl.
  • Aryl indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups.
  • Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl, 2-naphthyl, and bi-phenyl.
  • a "carbocyclyl” is a monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring system in which all ring atoms are carbon. Usually each ring of the carbocyclyl group contains from
  • 3- 6 ring atoms and a bicyclic carbocyclyl group contains from 7 to 10 ring atoms, but some other number of ring atoms may be specified.
  • the carbocycle may be attached to the group it substitutes at any carbon atom that results in a stable structure.
  • the carbocyclic rings described herein may be substituted at any carbon atom if the resulting compound is stable.
  • Examples of carbocyclyl groups include phenyl, naphthyl, tetrahydronaphthyl, cyclopropyl, cyclohexyl, and cyclohexenyl.
  • Cycloalkyl is a saturated hydrocarbon ring group, having the specified number of carbon atoms.
  • Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 6 (3, 4, 5, or 6) carbon ring atoms.
  • Cycloalkyl substituents may be pendant from a substituted nitrogen, oxygen, or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group, which is attached as a spiro group.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Halo or "halogen” indicates any of fluoro, chloro, bromo, and iodo.
  • Haloalkyl indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and penta-fluoroethyl.
  • Haloalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • heterocyclyl indicates a monocyclic saturated, partially unsaturated, or aromatic ring containing from 1 to 4 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a bicyclic saturated, partially unsaturated, or aromatic heterocycle containing at least 1 heteroatom chosen from N, O, and S in one of the two rings of the two ring system and containing up to about 4 heteroatoms independently chosen from N, O, and S in each ring of the two ring system.
  • each ring of the heterocycle contains from 4-6 ring atoms but some other number of ring atoms may be specified.
  • the heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocycles described herein may be substituted on carbon, sulfur, or nitrogen atom if the resulting compound is stable. It is preferred that the total number of heteroatoms in a heterocycle is not more than 4 and that the total number of S and O atoms in a heterocycle is not more than 2, more preferably not more than 1.
  • heterocyclyl groups include, pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.
  • a heterocycle is chosen from pyridinyl, pyrimidinyl, fur
  • heterocyclyl groups include, but are not limited to, phthalazinyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl,
  • the heterocyclyl group is a pyrimidinyl, oxazolyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, isothiazolyl, pyrrolidinyl, oxadiazolyl, oxadiazolyl, oxadiazolyl substituted with benzyl, pyrazolyl, pyrazinyl, oxazolidinyl, isothiazolidinyl, imidiazolyl, pyridazinyl, pyridinyl, pyrrolyl, thiazolyl, thienyl, or furanyl group.
  • Heteroaryl is a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 4, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 4, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon.
  • Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In certain embodiments there heteroaryl group is a 5- or 6- membered heteroaryl group having 1, 2, 3, or 4 heteroatoms chosen from N, O, and S, with no more than 2 O atoms and 1 S atom.
  • a "hydrocarbyl” group is hydrocarbon chain having the specified number of carbon atoms in which carbon atoms are joined by single, double or triple bonds, and any one carbon atom can be replaced by O, NH, or N(Ci-C 4 alkyl).
  • mono- and/ or di-alkylamino indicates secondary or tertiary alkyl amino groups, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • an oxo group substitutes a heteroaromatic moiety the resulting molecule can sometimes adopt tautomeric forms.
  • a pyridyl group substituted by oxo at the 2- or 4-position can sometimes be written as a pyridine or hydroxypyridine.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent.
  • substituents are named into the core structure.
  • aminoalkyl means the point of attachment of this substituent to the core structure is in the alkyl portion and alkylamino means the point of attachment is a bond to the nitrogen of the amino group.
  • Suitable groups that may be present on a "substituted" or “optionally substituted” position include, but are not limited to, e.g., halogen; cyano; -OH; oxo; -NH2; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); C(0)N3 ⁇ 4; alkyl groups (including cycloalkyl and (cycloalkyl)alkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages and from 1 to about 8 carbon atoms, or from 1 to about
  • "optionally substituted” includes one or more substituents independently chosen from halogen, hydroxyl, oxo, amino, cyano, -CHO, -CO2H, -C(0)NH2, Ci-Ce-alkyl, C2-Ce-alkenyl, Ci-Ce-alkoxy, C2-Ce-alkanoyl, Ci-Ce- alkylester, (mono- and di-Ci-C6-alkylamino)Co-C2-alkyl, (mono- and di-Ci-C6-alkylamino)(CO)Co-C2- alkyl, Ci-C2-haloalkyl, Ci-C2haloalkoxy, and heterocyclic substituents of 5-6 members and 1 to 3 N, O or S atoms, i.e.
  • pyridyl pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, mo ⁇ holinyl, piperazinyl, and pyrrolidinyl, each of which heterocycle can be substituted by amino, Ci-Ce-alkyl, Ci-Ce-alkoxy,.or - CONH2.
  • "optionally substituted” includes halogen, hydroxyl, cyano, nitro, oxo, -CONH2, amino, mono- or di-Ci-C4alkylcarboxamide, and Ci-Cehydrocarbyl , which Ci-Cehydrocarbyl group, a hydrocarbon chain in which carbon atoms are joined by single, double or triple bonds, and any one carbon atom can be replaced by O, NH, or N(Ci-C4alkyl) and which hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, halogen, and amino.
  • a "dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
  • “Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt, solvate, or hydrate of Formula (I) or a prodrug thereof, and at least one other substance, such as a carrier. Pharmaceutical compositions optionally contain one or more additional active agents. When specified, pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat a disorder, such as a Gram-negative bacterial infection.
  • “Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines or nitrogen-containing heteroaryl rings (e.g. pyridine, quinoline, isoquinoline); alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, H02C-(CH2) n -C02H where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al, Journal of
  • carrier applied to pharmaceutical compositions/combinations of the disclosure refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a "patient” is a human or non-human animal in need of medical treatment.
  • the patient is a human patient.
  • Providing means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.
  • Treatment includes providing a compound of this disclosure such as a compound of any of formula I, either as the only active agent or together with at least one additional active agent sufficient to: (a) inhibiting the disease, i.e. arresting its development; and (b) relieving the disease, i.e., causing regression of the disease and in the case of a bacterial infection to eliminate or reduce the virulence of the infection in the subject.
  • Treating and “treatment” also means providing a therapeutically effective amount of a compound of the disclosure as the only active agent or together with at least one additional active agent to a subject having or susceptible to a bacterial infection.
  • “Prophylactic treatment” includes administering an amount of a compound of the disclosure sufficient to significantly reduce the likelihood of a disease from occurring in a subject who may be predisposed to the disease but who does not have it.
  • a "therapeutically effective amount" of a pharmaceutical composition/ combination is an amount effective, when administered to a subject, to provide a therapeutic benefit, such as to decrease the morbidity and mortality associated with bacterial infection and/ or effect a cure.
  • a subject suffering from a microbial infection may not present symptoms of being infected.
  • a therapeutically effective amount of a compound is also an amount sufficient to significantly reduce the detectable level of microorganism in the subject's blood, serum, other bodily fluids, or tissues.
  • the disclosure also includes, in certain embodiments, using compounds of the disclosure in prophylactic treatment and therapeutic treatment.
  • a "therapeutically effective amount” is an amount sufficient to significantly decrease the incidence of or morbidity and mortality associated with bacterial infection.
  • prophylactic treatment may be administered when a subject is known to be at enhanced risk of bacterial infection, such cystic fibrosis or ventilator patients.
  • a significant reduction is any detectable negative change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • variables, R 1 and R 2 and variables such as R 3 , R 4 , R 5 , R 6 , and R 7 that appear within the definitions of R 1 and R 2 ) carry any of the following definitions. Definitions for the variables may be combined in any matter that results in a stable compound encompassed by the scope of formula I as defined in the SUMMARY section.
  • R 1 is selected from hydrogen and methyl.
  • R 2 is -W-X-Y.
  • R 2 is W-X-Y and is selected from: -C(0)NH-N(R 4 )-C(0)R 6 ;
  • R 3 is an optionally substituted 4-, 5- or 6-membered heterocyclyl group having 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S .
  • R 3 is a heterocyclyl selected from oxazol-2-yl, l,2,4-oxadiazol-3-yl, pyridin-l-yl, azetidin- l-yl, and pyrrolidin-l-yl, and wherein R 3 is optionally substituted.
  • R 3 is 5-methyl-oxazol-2-yl, 5 -methyl- l,2,4-oxadiazol-3-yl, 2-oxo-pyridin-l-yl, 2-oxo- azetidin-l -yl, and 2-oxo-pyrrolidin-l -yl.
  • R 3 is-CH(OH)CH 3 or -CH(CH 3 ) 2 .
  • R 4 is independently selected at each occurrence from hydrogen and methyl.
  • R 5 is selected from methyl, -CH(CH 3 )-CF 3 , and -CH(CH 3 )(CF 3 )-CF 3 .
  • R 6 is selected from -CH 3 , -NHCH 3 , -CH 2 CF 3 , tetrahydrofuranyl, furanyl, and cyclopropyl.
  • R 2 is optionally substituted -C(0)heterocyclyl or optionally substituted -C(0)phenyl.
  • R 2 is optionally substituted -C(0)heterocyclyl or optionally substituted -C(0)phenyl and the heterocyclyl of the -C(0)heterocyclyl is an optionally substituted 5- or 6-membered heterocyclyl group having group having 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S.
  • R 2 is optionally substituted -C(0)heterocyclyl and heterocyclyl of the
  • -C(0)heterocyclyl is chosen from pyrimidinyl, oxazolyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, isothiazolyl, pyrrolidinyl, oxadiazolyl, oxadiazolyl, oxadiazolyl substituted with benzyl, pyrazolyl, pyrazinyl, oxazolidinyl, isothiazolidinyl, imidiazolyl, pyridazinyl, pyridinyl, pyrrolyl, thiazolyl, thienyl, and furanyl, each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, oxo,
  • Ci-Cehydrocarbyl which Ci-Cehydrocarbyl group, a hydrocarbon chain in which carbon atoms are joined by single, double or triple bonds, and any one carbon atom can be replaced by O, NH, or N(Ci-C4alkyl) and which hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, halogen, and amino.
  • R 2 is selected from -C(0)heterocyclyl, -heterocyclyl, and -C(0)-phenyl, wherein each heterocyclyl is selected from pyrimidin-2-yl, oxazol-4-yl, morpholin-3-yl, isothiazol-3-yl, pyrrolidin-2-yl, l,2,4-oxadiazol-3-yl, pyrazol-4-yl, pyrazin-2-yl, oxazolidin-4-yl, isothiazolidin-3-yl, pyridazin-3-yl, pyridin-2-yl, and furan-2-yl; and wherein each heterocyclyl or phenyl is optionally substituted.
  • R 2 is selected from -C(0)heterocyclyl, -heterocyclyl, and -C(0)-phenyl, wherein each heterocyclyl is selected from pyrimidin-2-yl, 2-acetylamino-pyrimidin-4-yl, 2-methyl-oxazol-4-yl, 2,5-dimethyl-oxazol-4-yl, 5-oxo-mo holin-3-yl, 5-methyl-isothiazol-3-yl, 5-oxo-pyrrolidin-2-yl, 4,4- dimethyl-5 -oxo-pyrrolidin-2-yl, 4-hydroxy-5 -oxo-pyrrolidin-2-yl, 2-hydroxymethyl-5 -oxo-pyrrolidin-2- yl, 3 -hydroxymethyl-5 -oxo-pyrrolidin-2-yl, 5 -methyl- 1 ,2,4-oxadiazol-3 -yl, 5 -methyl-2-ox
  • R 1 and R 2 are taken together to form a ring selected from pyrrolidinyl and pyridinyl, wherein the ring is optionally substituted.
  • R 1 and R 2 are taken together to form a ring selected from 2-oxo-3-aminoacetyl-4- hydroxymethyl-pyrrolidinyl, 2-oxo-3-aminoacetyl-pyrrolidinyl and 2-oxo-3-acetylamino-pyridinyl.
  • the disclosure also includes compounds in which, when R 2 is W-X-Y and W is - C(O), X is CH(OH)CH 3 and Y is -NR 4 C(0)R 6 , the R 6 is not methyl, 2-aminocyclopentyl,
  • the disclosure also includes compounds in which when R 2 is W-X-Y and W is - C(O), X is CH(OH)CH 3 and Y is -NR 4 C(0)R 6 , the R 6 is not methyl, ethyl, or a group containing a cyclopentyl, cyclohexyl, or piperidinyl moiety.
  • R 2 is selected from optionally substituted -C(0)-heterocyclyl, optionally
  • R 2 is selected from -C(0)NH-N(R 4 )-C(0)R 6 and - W-X-Y.
  • the substituted aryl is substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, oxo, -CONH2, amino, ono- or di-Ci-C4alkylcarboxamide, and Ci- Cehydrocarbyl , which Ci-Cehydrocarbyl group, a hydrocarbon chain in which carbon atoms are joined by single, double or triple bonds, and any one carbon atom can be replaced by O, NH, or N(Ci-C4alkyl) and which hydrocarbyl group is optionally substituted with one or more substituents independently chosen from hydroxyl, halogen, and amino and at least one substituent is other than methyl.
  • R 2 is selected from -C(0)-heterocyclyl, -heterocyclyl, and -C(0)-aryl; or R 2 is selected from -C(0)NH-N(R 4 )-C(0)R 6 and -W-X-Y and when R 2 is W-X-Y, and W is C(O), X is - CH(OH)CH 3 or -CH(CH 3 ) 2 and Y is-N(R 4 )(R 5 ), N(R 4 )C(0)R 6 , or -N(R 4 )-S(0) 2 -R 6 , R 5 is not alkyl and R 6 is not alkyl or -NH(alkyl).
  • R 2 is -W-X-Y, wherein
  • W is C(O);
  • X is CH(R 3 ), wherein R 3 is selected from -CH(OH)CH 3 , and
  • Y is -N(R 4 )C(0)R 6 , wherein R 4 at each occurrence is hydrogen, and R 6 is selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an isoindolyl group, an indolyl group, an indazolyl group, a purinyl group, a quinolinyl group, an isoquinolinyl group, a benzoquinolinyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, a phenanthridinyl group, an acridinyl group, a
  • benzothienopyrimidinyl group a phenoxazinyl group, a pyridobenzoxazinyl group, and a
  • pyridobenzothiazinyl group each optionally substituted with at least one selected from deuterium, -F, -CI, -Br, -I, a hydroxy group, a cyano group, a nitro group, an amino group, an amidino group, a hydrazine group, a hydrazone group, a carboxylic acid group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, a Ci-Cio alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C10 alkoxy group, a phenyl group, a biphenyl group, a terphenyl group, a naphthyl group, an anthracenyl group, a pyrenyl group, a phenanthrenyl group, a fluorenyl group, a
  • R 2 carries the definition given in definition (22) wherein R 6 is represented by one of the following formulae:
  • a pyrrolyl group an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an isoindolyl group, an indolyl group, an indazolyl group, a purinyl group, a quinolinyl group, an isoquinolinyl group, a benzoquinolinyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a carbazolyl group, a phenanthridinyl group, an acridinyl group, a phenanthrolinyl group, a phenazinyl group, a benzoxazolyl group, a benzoimidazoly
  • benzothienopyrimidinyl group a phenoxazinyl group, a pyridobenzoxazinyl group, and a
  • pyridobenzothiazinyl group each optionally substituted with at least one selected from deuterium, -F, -CI, -Br, -I, a hydroxy group, a cyano group, a nitro group, an amino group, an amidino group, a hydrazine group, a hydrazone group, a carboxylic acid group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, a Ci-Cio alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C10 alkoxy group, a phenyl group, a biphenyl group, a terphenyl group, a naphthyl group, an anthracenyl group, a pyrenyl group, a phenanthrenyl group, a fluorenyl group, a
  • the disclosure includes a pharmaceutical composition containing at least one compound of formula I as the active agent together with a pharmaceutically acceptable carrier.
  • compositions of the disclosure include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), inhalable, and injection (intraperitoneally, subcutaneously, intramuscularly or parenterally) formulations.
  • the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, sterile ocular solution, parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto- injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.
  • the dosage form containing the composition of the disclosure contains an effective amount of the active agent necessary to provide a therapeutic effect by the chosen route of administration.
  • the composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the disclosure or salt form thereof and may be constituted into any form suitable for the selected mode of administration.
  • the dosage form may be formulated for immediate release or controlled release, including delayed release or sustained release.
  • the pharmaceutical composition may include a compound for formula I as the only active agent or may be combined with one or more additional active agents.
  • the pharmaceutical composition includes a compound of formula I and at least one direct acting antibiotic (a compound efficacious for killing pathogenic bacteria in vivo).
  • the disclosure includes a method of treating a bacterial infection in a subject by administering an effective amount of one or more compounds of the disclosure to a subject at risk for a bacterial infection or suffering from a bacterial infection.
  • the disclosure includes a method of treatment in which a compound of formula I is used to sensitize bacteria to an antibacterial agent.
  • a compound of formula I is administered to a patient having a bacterial infection, simultaneously or sequentially, with a therapeutically effective amount of the antibacterial agent.
  • the compound of formula I increases the efficacy, often by lowering the MIC, of the other antibacterial agent.
  • Treatment of human patients is particularly contemplated. However, treatment of non-human subjects is within the scope of the disclosure.
  • the disclosure includes treatment or prevention of microbial infections in fish, amphibians, reptiles or birds, but a preferred embodiment of the disclosure includes treating mammals.
  • the bacterial infection or antibiotic-tolerant or antibiotic-resistant infection is caused by a Gram-negative bacterium.
  • the microbial infection is the result of a pathogenic bacterial infection.
  • pathogenic bacteria include, without limitation, bacteria within the genera Aerobacter, Aeromonas, Acinetobacter, Agrobacterium, Bacillus, Bacteroides, Bartonella, Bordetella, Brucella, Burkholderia, Calymmatobacterium, Campylobacter, Citrobacter, Clostridium, Corynebacterium, Enter obacter, Enterococcus, Escherichia, Francisella, Haemophilus, Hafnia, Helicobacter, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Staphylococcus, Streptococcus, Treponema, Xanthomonas, Vibrio, and Yersinia.
  • Such bacteria include Vibrio harveyi, Vibrio cholerae, Vibrio parahemolyticus, Vibrio alginolyticus, Pseudomonas phosphoreum, Pseudomonas aeruginosa, Yersinia enterocolitica, Escherichia coli, Salmonella typhimurium, Haemophilus influenzae, Helicobacter pylori, Bacillus sub ti lis, Borrelia burgdorferi, Neisseria meningitidis, Neisseria gonorrhoeae, Yersinia pestis, Campylobacter jejuni, Mycobacterium tuberculosis, Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Klebsiella pneumoniae, Burkholderia cepacia, Acinetobacter baumannii, Staphylococcus
  • the Gram-negative bacterium is a. Pseudomonas, e.g., P.
  • the Gram-negative bacterium is Burkholderia species.
  • the Gram-negative bacterium is Acinetobacter, e.g., A. baumannii.
  • the Gram-negative bacterium is an Enterobacteriaceae, e.g.,
  • Klebsiella pneumonia e.g., Escherichia coli, e.g., Enterobacter cloacae, e.g., Serratia marcescens, e.g., Salmonella typhimurium, e.g., Shigella dysenteriae, e.g., Proteus mirabilis, e.g., Citrobacter freundii, e.g., Yersinia pestis.
  • Escherichia coli e.g., Enterobacter cloacae
  • Serratia marcescens e.g., Salmonella typhimurium, e.g., Shigella dysenteriae, e.g., Proteus mirabilis, e.g., Citrobacter freundii, e.g., Yersinia pestis.
  • the infection is a polymicrobial infection, e.g., an infection comprising more than one organism.
  • the infection comprises at least one of the organisms listed above, e.g., one or more of Pseudomonas, e.g., P. aeruginosa, Klebsiella, e.g., Klebsiella pneumoniae, and/or Acinetobacter, e.g., A. baumannii.
  • the methods further include administering an additional active agent in combination with a compound of the disclosure, such as an antibiotic selected from the group consisting of but not limited to: beta-lactams such as penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, quinolones including fluoroquinolones and similar DNA synthesis inhibitors, tetracyclines, aminoglycosides, macrolides, glycopeptides, chloramphenicols, glycylcyclines, lincosamides, lipopeptides, lipodepsipeptides, such as daptomycin, and oxazolidinones.
  • an antibiotic selected from the group consisting of but not limited to: beta-lactams such as penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, quinolones including fluoroquinolones and similar DNA
  • the bacterial infection is an upper and lower respiratory tract infection, pneumonia, bacteremia, a systemic infection, sepsis and septic shock, a urinary tract infection, a gastrointestinal infection, endocarditis, a bone infection, central nervous system infections such as meningitis, or an infection of the skin and soft tissue.
  • the subject is a mammal, e.g., a human or non-human mammal.
  • the methods include treating one or more cells, e.g., cells in a culture dish.
  • the present disclosure features a method of treating a Gram-negative infection in a subject, the method comprising administering to said subject in need of such treatment a therapeutically effective amount of a compound described herein.
  • the Gram-negative infection is caused by Pseudomonas aeruginosa.
  • the disclosure includes treating an infection caused by Gram- positive bacteria, such as Staphylococcus epidermidis and Staphylococcus aureus.
  • the subject is a trauma patient or a burn patient suffering from a burn or skin wound.
  • the present disclosure features a method of reducing bacterial tolerance in a subject, the method comprising administering to said subject a therapeutically effective amount of a compound described herein.
  • the method further includes identifying said subject suffering from an infection with bacteria resistant to antimicrobial therapy.
  • the disclosure includes methods of treatment in which a compound or composition of the disclosure is administered orally, topically, intravenously, parenterally, or inhaled.
  • a compound of the disclosure may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed. Frequency of dosage may also vary depending on the compound used, the particular disease treated and the bacteria causing the disease. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • Compound 1 is not compound of Formula I.
  • the synthesis of this compound is provided to exemplify a synthetic method by which many compounds of Formula I can be prepared.
  • Step 1 Synthesis of tert-butyl 2,2',2"-((2S,5R,8S, l lS,14S, 17S,22S)-5-benzyl-17-((R)-l- hydroxyethyl)-8-isobutyl-22-(2-(3-methyl-lH-pyrazol-l-yl)acetamido)-3,6, 9,12, 15,18,23-heptaoxo- 1,4,7,10, 13, 16, 19-heptaazacyclotricosane-2,l l, 14-triyl)tris(ethane-2, l-diyl)tricarbamate.
  • Step 2 Synthesis of 2-(3-methyl-lH-pyrazol-l-yl)-N-((3S,6S,9S,12S,15R,18S,21S)- 6,9, 18-tris(2-aminoethyl)-15-benzyl-3-((R)-l-hydroxyethyl)-12-isobutyl-2,5,8, 11,14, 17,20-heptaoxo- -yl)acetamide. (Compound 1) .
  • Step 1 Synthesis of (R)-methyl 2-((2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy butanamido)-3-(tert-butyldiphenylsilyloxy)propanoate (Intermediate Compound 8).
  • Step 2 Synthesis of (R)-methyl 2-((2S,3R)-2-amino-3-hydroxybutanamido)-3-(tert- butyldiphenylsilyloxy)propanoate (Intermediate compound 9).
  • Step 3 Synthesis of (R)-methyl 3-(tert-butyldiphenylsilyloxy)-2-((2S,3R)-2-(furan-2- carboxamido)-3-hydroxybutanamido)propanoate (Intermediate Compound 11).
  • Step 4 Synthesis of (R)-3-(tert-butyldiphenylsilyloxy)-2-((2S,3R)-2-(furan-2-carbox amido)-3-hydroxybutanamido)propanoic acid (Intermediate Compound 12).
  • Step 5 Synthesis of tert-butyl 2,2',2"-((2S,5R,8S, l lS, 14S, 17S,22S)-5-benzyl-22-((R)-3- (tert-butyldiphenylsilyloxy)-2-((2S,3R)-2-(furan-2-carboxamido)-3-hydroxy butanamido)propanamido)- 17-((R)-l-hydroxyethyl)-8-isobutyl-3,6,9, 12,15, 18,23-heptaoxo-l,4,7, 10, 13,16, 19- heptaazacyclotricosane-2, l l,14-triyl)tris (ethane-2, l-diyl)tricarbamate (Intermediate Compound 13).
  • Step 6 Synthesis of tert-butyl 2,2',2"-((2S,5R,8S,l lS,14S, 17S,22S)-5-benzyl-22-((R)-2- ((2S,3R)-2-(furan-2-carboxamido)-3-hydroxybutanamido)-3-hydroxypro panamido)-17-((R)-l- hydroxyethyl)-8-isobutyl-3,6,9, 12,15, 18,23-heptaoxo-l,4,7,10, 13, 16, 19-heptaazacyclotricosane-2, l l,14- triyl)tris(ethane-2, l-diyl) tricarbamate (Intermediate Compound 14).
  • Step 7 Synthesis of N-((2S,3R)-3-hydroxy-l-((R)-3-hydroxy-l-oxo-l- ((3S,6S,9S, 12S, 15R, 18S,21S)-6,9, 18-tris(2-aminoethyl)-15-benzyl-3-((R)-l-hydroxyethyl)-12-iso butyl- 2,5,8,11, 14,17,20-heptaoxo- 1, 4,7, 10,13, 16, 19-heptaazacyclotricosan-21 -ylamino)propan-2-ylamino)- 1 - .
  • N-((R)-3-hydroxy-l-oxo-l-((3S,6S,9S,12S,15R,18S,21S)-6,9,18-tris(2-aminoethyl)-15- benzyl-3-((R)-l-hydroxyethyl)-12-isobutyl-2,5,8,ll,14,17,20-heptaoxo-l,4,7,10,13,16,19- heptaazacyclotricosan-21 -ylamino)propan-2-yl)-6-methylpyrazine-2-carboxamide was prepared according to the coupling then deprotection sequence described for Example 7, Compound 15.
  • Step 1 Synthesis of Intermediate Compound 33.
  • D-serine methyl ester hydrochloride 30 5 g, 40.7 mmol
  • ethyl acetimidate hydrochloride 31 6.18 g, 50 mmol
  • CH2CI2 100 mL
  • triethylamine 12.4 mL, 89.5 mmol
  • CH2CI2 35 mL
  • Step 2 Synthesis of Intermediate Compound 34.
  • methyl 2- methyloxazole-4-carboxylate 33 1.2 g, 8.5 mmol
  • methanol 6 mL
  • water 6 mL
  • LiOH 5 10 mg, 21.3 mmol
  • the reaction mixture was stirred at room temperature for 2 h.
  • the crude mixture was acidified by 2M HC1 to adjust pH to 5.
  • the resulting mixture was extracted with DCM/i-PrOH (100 mL, 3 : 1 v/v).
  • Step 1 Synthesis of Intermediate Compound 43.
  • L-Serine 41 2.3 g, 17.32 mmol
  • 4methoxybenzaldehyde 42 (2 g, 19.05mmol).
  • the resulting mixture was stirred at room temperature overnight.
  • Sodium borohydride (1.64 g, 26 mmol) was added portionwise such that an internal temperature of below 10 °C.
  • the reaction mixture was allowed to stir at room temperature for 1 h.
  • the crude mixture was extracted with Et20 (100 mL) and the aqueous phase was acidified by Cone. HC1 to adjust pH to 5.
  • the resultant white precipitate was filtered and washed with water.
  • Step 4 Synthesis of Intermediate Compound 46.
  • (S)- benzyl 4-(4-methoxybenzyl)-5-oxomorpholine-3-carboxylate 45 (886 mg, 2.5 mmol) in the mixture of CH 3 CN (1 1 mL) and water (1 1 mL)
  • CAN (6.84 g, 12.5 mmol).
  • the reaction mixture was stirred at this temperature for 1 h.
  • the crude mixture was diluted with water ( 100 mL), the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered, and then concentrated to dryness.
  • Step 1 Synthesis of Intermediate Compound 54.
  • benzyl 3-oxobutanoate 53 (1.46 g, 7.6 mmol) in glacial AcOH (5 mL) stirred at 0 °C was added a solution of NaNC (1.31 g, 19.0 mmol) in water (4 mL) dropwise over a period of 1 h. The resulting mixture was stirred at amibient temperature overnight. The reaction mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL).
  • Step 2 Synthesis of Intermediate Compound 55.
  • Zn powder (2.47 g, 38 mmol) was slowly added to a solution of (E)-benzyl 2-(hydroxyimino)-3-oxobutanoate 53 (1.68 g, 7.6 mmol) and acetic anhydride (1.9 g, 19 mmol) in glacial AcOH (4 mL), and the resulting mixture was stirred room temperature for 3 h.
  • the crude mixture was poured into ice water, filtrated through Celite, and the solid residue washed with dichloromethane (50 mL).
  • the organic layer was separated, and the aqueous mixture was extracted with dichloromethane (50 mL).
  • Step 3 Synthesis of Intermediate Compound 56.
  • Triethylamine (323 mg, 3.2 mmol) was added to a solution of triphenylphosphine (419 mg, 1.6 mmol) and iodine (406 mg, 1.6 mmol) in dry dichloromethane (5 mL) and stirred for 30 min. Then a solution of the benzyl 2-acetamido-3- oxobutanoate 55 (200 mg, 0.8 mmol) in dry dichloromethane (4 mL) was added and the reaction mixture stirred until completion of reaction (followed by TLC).
  • Step 4 Synthesis of Intermediate Compound 57.
  • Pd/C (10% w/w, 150 mg) was added to a solution of benzyl 2,5-dimethyl oxazole-4-carboxylate 56 (2.1 g, 9 mmol) in dry ethyl acetate (10 mL) and stirred at room temperature under atmospheric pressure of hydrogen overnight.
  • the catalyst was filtered off through Celite and washed with methanol (2 mL). The filtrates were concentrated to dryness to give title compound 57, 2,5-dimethyloxazole-4-carboxylic acid (1.1 g, 84% yield).
  • LC-MS (LC method 1) m/z 142 (M+l) + .
  • Step 1 Synthesis of Intermediate Compound 66.
  • furan-2-carbonitrile 64 5 g, 53.7 mmol
  • pentane-2,4-dione 65 6.45 g, 53.7 mmol
  • AICI3 7.1 g, 53.7 mmol
  • the resulting mixture was stirred at 100 °C for 4 h.
  • the crude mixture was quenched with 4 M HC1 and stirred for 4 h.
  • the resulting mixture was extracted with ethyl acetate (3 x 100 mL) The combined organic phase were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated to dryness.
  • Step 2 Synthesis of Intermediate Compound 67.
  • P2S5 (1.11 g, 5 mmol).
  • the resulting mixture was stirred at room temperature for 36 h.
  • the crude mixture was concentrated to dryness, the residue was dissolved in MTBE (30 mL), treated with 30% H2O2 (20 mL), the reaction mixture was stirred for additional 30 h.
  • the crude mixture was quenched with aq. Na2S2C>3 carefully, extracted with ethyl acetate (100 mL x 2).
  • the combined organic phase were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated to dryness.
  • Step 3 Synthesis of Intermediate Compound 68.
  • a mixture of 3-(furan-2-yl)-5- methylisothiazole 67 (0.4 g, 2.4 mmol) in acetone 10 (mL) and water (20 mL) was added KMn04 (0.77 g, 4.8 mmol).
  • the reaction mixture was stirred for 1.5 h at room temperature.
  • 2 M NaOH (25 mL) was added and heated to 50 °C for 1.5 h.
  • the resulting mixture was acidified with 2M HCl and extracted with ethyl acetate (100 mL). The organic extract was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated to give title compound 68, 5 -methylisothiazole-3 -carboxylic acid (0.2 g).
  • Step 1 Synthesis of Intermediate Compound 76.
  • SOC SOC (16.7 g, 130 mmol at 0°C, and the reaction mixture was stirred at this temperature for additional 3 h.
  • the crude mixture was concentrated to dryness, the residue was dissolved in DCM (300 mL).
  • the organic layer was washed brine and dried over anhydrous Na2SC>4, filtered and concentrated to dryness to give title compound 76, (S)-ethyl 5-oxopyrrolidine-2-carboxylate (13 g, 82% yield).
  • Step 2 Synthesis of Intermediate Compound 77.
  • (S)-ethyl 5- oxopyrrolidine-2-carboxylate 76 15 g, 95.54 mol
  • dimethylaminopyridine 1.166 g, 9.554 mol
  • B0C2O 20.85 g, 95.54 mol
  • the resulting mixture was stirred at room temperature overnight.
  • the crude mixture was washed with saturated NH4CI solution.
  • the organic phase was separated, dried over anhydrous Na2SC>4, filtered and concentrated.
  • Step 3 Synthesis of Intermediate Compound 78.
  • (S)-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate 77 (5.1 g, 20 mmol) in dry THF (100 mL) stirred at -78 °C was added lithium hexamethyldisilazide (44 mL, 44 mmol, 1 M in THF).
  • Step 4 Synthesis of Intermediate Compound 79.
  • TFA 1.5 mL
  • the reaction mixtures were stirred at room temperature overnight.
  • the crude mixture was concentrated to dryness to give title compound 79, (S)-ethyl 4,4-dimethyl-5-oxopyrrolidine-2- carboxylate (400 mg, 95% yield) without further purification.
  • LC-MS LC method 1): m/z 186 (M+l) + .
  • Step 5 Synthesis of Intermediate Compound 80.
  • EtOH EtOH
  • aq. LiOH 5 mL, 4M solution.
  • the reaction mixture was stirred at room temperature for 2 h.
  • the crude mixture was acidified with 2M HC1 to adjust the pH to ⁇ 5.
  • the resulting mixture was extracted with DCM/i-PrOH (50 mL, 3 : 1 v/v).
  • Step 1 Synthesis of Intermediate Compound 88.
  • ethyl cyanoformate 87 (4 g, 40 mmol) in the mixture of ethanol (43 mL) and water (27 mL)
  • hydroxylamine hydrochloride (5.6 g, 80 mmol)
  • sodium carbonate 3.3 g, 40 mmol
  • Step 2 Synthesis of Intermediate Compound 89.
  • a mixture of compound 88 (1 g, 7.5 mmol) and AC2O (5 mL) was stirred at room temperature for 30 min.
  • the crude mixture was concentrated to give title compound 89, (Z)-ethyl 2-(acetoxyimino)-2-aminoacetate (700 mg), which used in the next step without purification.
  • Step 3 Synthesis of Intermediate Compound 90.
  • a mixture of compound 89 (644 mg, 3.7 mmol) and HO Ac (3 mL) was heated at 130 °C under microwave for 1.5 h.
  • LC-MS LC method 1): m/z 157 (M+l) + .
  • Step 4 Synthesis of Intermediate Compound 91.
  • a solution of compound 90 (780 mg, 5 mmol) in EtOH (1 mL) was added 10 M KOH (1 mL) at room temperature. After being stirred at room temperature for 15 min, the reaction mixture was filtered to give the title compound potassium 5-methyl- l,2,4-oxadiazole-3-carboxylate 5 (500 mg, 64% yield).
  • LC-MS (LC method 1): m z 129 (M+l) + .
  • Step 1 Synthesis of Intermediate Compound 106.
  • compound 105 (10 g, 43.3 mmol) DMF (150 mL)
  • K 2 C0 3 (12 g, 86.6 mmol)
  • Mel 6.1 g, 43.3 mmol
  • the resulting mixture was stirred at room temperature overnight.
  • the crude mixture was diluted with water (500 mL), extracted with DCM (500 mL).
  • the organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated to dryness to give title compound 106, (2S,4R)-l-tert-butyl 2-methyl 4- hydroxypyrrolidine-l,2-dicarboxylate (10.5 g) without further purification.
  • LC-MS (LC method 1): m/z 246 (M+l) + .
  • Step 3 Synthesis of Intermediate Compound 108.
  • NalC 1.5 g, 7.0 mmol
  • RuC .LbO 75 mg, 0.56 mmol
  • the resulting green-yellow solution was stirred at room temperature for 5 min followed by addition of (2S,4R)- l-tert-buty2-methyl4-((tert-butyldimethyl silyl)oxy)pyrrolidine - 1,2-dicarboxylate 107 (1.0 g, 2.8 mmol) in EtOAc (8 mL) in one portion. The mixture was stirred at room temperature overnight.
  • Step 4 Synthesis of Intermediate Compound 109.
  • (2S,4R)-l-tert-butyl 2-methyl 4-(tert-butyldiphenylsilyloxy)-5-oxopyrrolidine- 1,2-dicarboxylate 108 (900 mg, 2.4 mmol) in THF (10 mL) was added TBAF (4.8 mL, 1 M THF solution). The resulting mixture was stirred at room temperature overnight. The crude mixture was quenched with aq. NH4CI (10 mL). The resulting mixture was extracted with ethyl acetate (100 mL).
  • Step 1 Synthesis of Intermediate Compound 119.
  • (R)-methyl 5- oxopyrrolidine-2-carboxylate 117 (4.2 g, 29.37 mmol) in dry THF (123 mL) stirred at -78 °C was added lithium hexamethyldisilazide (62.5 mL, 62.5 mmol, 1 M in THF). After addition, the reaction mixture was warmed to -30 °C over lh. Then the reaction mixture was cooled to -78 °C again, and
  • Step 2 Synthesis of Intermediate Compound 120.
  • methyl 2- (benzyloxymethyl)-5-oxopyrrolidine-2-carboxylate 119 500 mg, 1.9 mmol
  • THF 10 mL
  • water 2 mL
  • Li OH 319 mg, 7.6 mmol
  • the reaction mixture was stirred at room temperature for 3 h.
  • the crude mixture was acidified by 2M HCl to adjusted pH to 3-4 and then extracted with ethyl acetate (50 mL).
  • Step 1 Synthesis of Intermediate Compound 131.
  • L-serine 130 (1.58 g, 15 mmol)
  • triphosgene(4.0 g, 15 rnmol) in dioxane (30 mL).
  • the reaction mixtures were stirred at room temperature until clear solutions were obtained and were further stirred for 2 h.
  • the crude mixture was concentrated to give title compound 131, (S)-2-oxooxazolidine-4-carboxylic acid (0.5 g, 8.5% yield) without further purification.
  • LC-MS LC method 1): m/z 132 (M+l) + .
  • Step 1 Synthesis of Intermediate Compound 140.
  • 2-hydrazinylethanol 139 5 g, 65.7 mmol
  • acetone 50 mL
  • Na2SC>4 23 g, 887.5 mmol
  • the resulting mixture was stirred at 0 °C overnight.
  • the crude mixtures was filtrated and concentrated to dryness to give title compound 139, 2-(2-(propan-2-ylidene)hydrazinyl)ethanol (5 g) without further purification.
  • LC-MS LC method 1): m/z 117 (M+l) + .
  • Step 3 Synthesis of Intermediate Compound 142.
  • Step 4 Synthesis of Intermediate Compound 144.
  • N-(2- hydroxyethyl)acetohydrazide 142 (4 g, 33.8 mmol) and (R)-methyl 2-amino-3-(tert- butyldiphenylsilyloxy)propanoate 143 (1.2 g, 3.38 mmol) in anhydrous DMF (25 mL) was added CDI (5.48 g, 33.8 mmol). The reaction mixture was stirred at room temperature overnight. The crude mixture was quenched with brine (100 mL) and extracted with ethyl acetate (250 mL). The organic phase was dried over anhydrous Na2SC>4, filtered, and then concentrated to dryness.
  • Step 1 Synthesis of Intermediate Compound 150.
  • (2S,3R)-2-amino-3-hydroxybutanoic acid 149 (2 g, 16.8 mmol) in 4 M Na2CC>3 (10 mL) was added a solution of MsCl (1.92 g, 16.8 mmol) in THF (5 mL) dropwise during 30 min. The resulting mixture was stirred at this temperature overnight.
  • Step 1 Synthesis of Intermediate Compound 158. To a solution compound 1 (2.9 g, 10 mmol) in DCM (15 mL) was added TFA (3 mL). The resulting mixture was stirred at this temperature overnight. The crude mixture was concentrated to dryness to provide crude 158, (S)-2-amino-3- (benzyloxy) propanoic acid (2 g). LC-MS (LC method 1): m/z 196 (M+l) + .
  • Step 4 Synthesis of Intermediate Compound 161.
  • DCM 50 mL
  • TEA 500 mg, 5.0 mmol
  • MsCl 0.33 g, 2.88 mmol
  • Step 5 Synthesis of Intermediate Compound 163.
  • 3- nitropyridin-2(lH)-one 162 450 mg, 3.2 mmol
  • 60% NaH 160 mg, 3.84 mmol
  • (S)-methyl 3-(benzyloxy)-2- (methylsulfonyloxy)propanoate 161 1.0 g, 3.0 mmol
  • the reaction mixture was stirred at room temperature overnight.
  • the crude mixture was quenched with sat. NH4CI (100 mL) and extracted with ethyl acetate (100 mL).
  • Step 6 Synthesis of Intermediate Compound 164.
  • Pd/C (10% w/w, 10 mg) was added to a solution of (R)-methyl 3-(benzyloxy)-2-(3-nitro-2-oxopyridin-l(2H)-yl)propanoate 7 (100 mg, 0.3 mmol) in MeOH (10 mL) and stirred at room temperature under atmospheric pressure of hydrogen overnight. The catalyst was filtered off through Celite and washed with methanol (2 mL).
  • Step 8 Synthesis of Intermediate Compound 166.
  • (R)-methyl 2-(3- acetamido-2-oxopyridin-l(2H)-yl)-3-(benzyloxy)propanoate 165 300 mg, 0.87 mmol
  • LiOH 35 mg, 0.87 mmol
  • the reaction mixture was stirred at room temperature for 3 h.
  • the crude mixture was acidified by 2M HCl to adjuste pH to 3-4 and then extracted with ethyl acetate (50 mL).
  • Step 1 Synthesis of Intermediate Compound 172.
  • LC-MS LC method 1): m/z 267 (M+l) + .
  • Step 2 Synthesis of Intermediate Compound 173.
  • Pd/C (10% w/w, 30 mg) was added to a solution of (2S,3R)-benzyl 3-hydroxy-2-(3-methylureido)butanoate 172 ( 160 mg, 0.6 mol) in MeOH (10 mL) and stirred at room temperature under atmospheric pressure of hydrogen overnight.
  • the catalyst was filtered off through Celite and washed with methanol (10 mL). The filtrates was concentrated to dryness to give title compound 173, (2S,3R)-3-hydroxy-2-(3-methylureido)butanoic acid (80 mg, 75.6 % yield).
  • LC-MS LC method 1): m/z 177 (M+l) + . 179
  • Step 1 Synthesis of Intermediate Compound 182.
  • DIPEA 3.54 g, 27.37 mmol
  • HOBt (2.22 g, 16.42 mmol)
  • HBTU (6.23 g, 16.42 mmol
  • Step 2 Synthesis of Intermediate Compound 183.
  • Step 3 Synthesis of Intermediate Compound 184.
  • Step 4 Synthesis of Intermediate Compound 185.
  • Step 1 Synthesis of Intermediate Compound 192.
  • DIPEA 7.56 g, 58.58 mmol
  • NaBH4 0.82 g, 21.48 mmol
  • the resulting mixture was stirred for 4 h.
  • the crude mixture was quenched with aq. NH4CI (50 mL) and extracted with ethyl acetate (200 mL x 2).
  • Step 2 Synthesis of Intermediate Compound 193.
  • (2S,3R)-methyl 2- (benzylamino)-3-hydroxybutanoate 192 (2.23g, 10 mmol) was in dry DMF (10 mL) was added Mel (1.4 g, 10 mmol) and NaHCC (2.5 g, 30 mmol). The reaction was stirred at room temperature overnight. The crude mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated to dryness.
  • Step 4 Synthesis of Intermediate Compound 195.
  • (2S,3R)-2- (benzyl(methyl)amino)-3-hydroxybutanoic acid 194 500 mg, 2.24 mmol
  • (S)-methyl 2-amino-3- (tert-butyldiphenylsilyloxy)pro panoate 800 mg, 2.24 mmol
  • DIPEA 866 mg, 6.72 mmol
  • HBTU HBTU
  • Step 5 Synthesis of Intermediate Compound 196 .
  • Pd/C (10% w/w, 200 mg) was added to a solution of (S)-methyl 2-((2S,3R)-2-(benzyl(methyl)amino)-3-hydroxybutanamido)-3-(tert- butyldiphenylsilyloxy) propanoate 195 (1 g, 1.78 mmol) in dry ethyl acetate (10 mL) and stirred at room temperature under atmospheric pressure of hydrogen overnight. The catalyst was filtered off through Celite and washed with methanol (10 mL).
  • Step 7 Synthesis of Intermediate Compound 198.
  • (S)-methyl 3-(tert- butyldiphenylsilyloxy)-2-((2S,3R)-3-hydroxy-2-(N-methylacetamido)butanamido)propanoate 197 350 mg, 0.68 mmol
  • LiOH 85.68 mg, 2.04 mmol
  • the reaction mixture was stirred at room temperature for 3 h.
  • the crude mixture was acidified by 2M HC1 to adjust pH to 3-4 and extracted with ethyl acetate (50 mL).
  • Step 1 Synthesis of Intermediate Compound 203.
  • imidazole 27 g, 38.5 mmol
  • TBDPSCl 35.8 g, 130 mmol
  • the resulting mixture was stirred at this temperature overnight.
  • the crude mixture was diluted with a sat. Li CI solution (500 mL).
  • the mixture was extracted with ethyl acetate (500 mL).
  • Step 2 Synthesis of Intermediate Compound 204.
  • (R)-methyl 2-(tert-butoxycarbonylamino) -3-(tert-butyldiphenylsilyloxy) propanoate 203 (4.58 g, 10 mmol) DCM (50 mL) was added TFA (0.97 g, 10 mmol). The resulting mixture was stirred at room temperature for 2 h.
  • the crude mixture was diluted with aq. NaHCC (100 mL) and extracted with DCM (500 mL). The organic phase was dried over anhydrous Na2SC>4, filtered, and concentrated.
  • Step 3 Synthesis of Intermediate Compound 206.
  • TEA 4.2 g, 41.6 mmol
  • B0C2O 9.1 g, 41.6 mmol
  • the resulting mixture was stirred at room temperature overnight.
  • the crude mixture was concentrated to dryness to give crude title compound 206, (S)-2-(tert- butoxycarbonylamino)-4-hydroxybutanoic acid (8.5 g).
  • LC-MS (LC method 1): m/z 220 (M+l) + .
  • Step 4 Synthesis of Intermediate Compound 207.
  • Step 6 Synthesis of Intermediate Compound 209.
  • NaHCC 26.9 mg, 0.32 mmol
  • the resulting mixture was stirred at 100 °C overnight.
  • the crude mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL).
  • Step 7 Synthesis of Intermediate Compound 210.
  • (S)-methyl 2-(tert- butoxycarbonylamino)-4-((R)-3 -(tert-butyldiphenylsilyloxy)- 1 -methoxy- 1 -oxopropan-2- ylamino)butanoate 209 50 mg, 0.087 mmol
  • m-Xylene 8 mL
  • DMAP 16.0 mg, 0.13 mmol
  • Step 8 Synthesis of Intermediate Compound 211.
  • (R)-methyl 2-((S)-3- (tert-butoxycarbonylamino)-2-oxopyrro lidin-l-yl)-3 -(tert-butyldiphenylsilyloxy )propanoate 210 (1 10 mg, 0.2 mmol) in DCM (5 mL) at room temperature was added TFA (1 16 mg, 1 mmol).
  • Step 9 Synthesis of Intermediate Compound 212.
  • pyridine 45.7 mg, 0.58 mmol
  • AC2O 29.5 mg, 0.29 mmol
  • Step 10 Synthesis of Intermediate Compound 213.
  • (R)-methyl 2-((S)- 3-acetamido-2-oxopyrrolidin-l-yl)-3-(tert-butyl diphenylsilyloxy) propanoate 212 (90 mg, 0.19 mmol) in the mixture of THF (3 mL) and water (3 mL) at 0 °C was added LiOH (4.5 mg, 0.19 mmol).
  • the reaction mixture was stirred at room temperature for 1 h.
  • the crude mixture was acidified by 2M HCl to adjuste pH to 3-4 and extracted with ethyl acetate (50 mL).
  • Step 1 Synthesis of Intermediate Compound 218.
  • TsCl (1.84 g, 9.64 mmol)
  • TEA 1.77 g, 17.53 mmol.
  • the resulting mixture was stirred at room temperature overnight.
  • the crude mixture was filtered; the filtrate was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase were washed with brine, dried over anhydrous Na2SC>4, filtered, and then concentrated.
  • Step 2 Synthesis of Intermediate Compound 220.
  • 1, 1, 1 -trifluoropropan- 2-yl 4-methylbenzenesulfonate 218 (1.24 g, 4.61 mmol) and (2S,3R)-benzyl 2-amino-3-hydroxybutanoate 219 (1.49 g, 4.61 mmol) in CH 3 CN (20 mL) was added NaHC0 3 (1.94 g, 23.05 mmol). The resulting mixture was stirred at 70 °C overnight.
  • the crude mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 2).
  • Step 3 Synthesis of Intermediate Compound 221.
  • Pd/C (10% w/w, 50 mg) was added to a solution of (2S,3R)-benzyl 3-hydroxy-2-(l, l, l-trifluoropropan-2-ylamino)butanoate 220 ( 700 mg, 2.29 mmol) in MeOH (10 mL) and stirred at room temperature under atmospheric pressure of hydrogen overnight. The catalyst was filtered off through Celite and washed with methanol (10 mL).
  • Step 1 Synthesis of Intermediate Compound 232.
  • phenylmethanol 230 (3 g, 27.74 mmol) in THF (10 mL)
  • 60% NaH 1.2 g, 50 mmol
  • THF 40 mL
  • the resulting mixture was stirred at this temperature for 0.5 h.
  • the crude mixture was added ethyl 2-bromoacetate 231 (4.63 g, 27.74 mmol).
  • the resulting mixture was stirred at room temperature for 4 h.
  • the crude mixture was quenched with 3 ⁇ 40 (20 mL), extracted with ethyl acetate (100 mL x 2).
  • Step 2 Synthesis of Intermediate Compound 233.
  • ethyl 2- (benzyloxy)acetate 232 (2.78g, 14.31mmol) was in dry DCM (47 mL), was added DIBAL-H (17 mL, 17.18mmol) at -78 °C dropwise during 10 min, The reaction was stirred for 1.5 h.
  • the reaction mixture was extracted with ethyl acetate (100 mL).
  • the organic phase was dried over anhydrous Na2SC>4, filtered, and concentrated to give crude title compound 233, 2-(benzyloxy)acetaldehyde (1.6 g).
  • LC-MS LC method 1): m/z 151 (M+l) + .
  • Step 3 Synthesis of Intermediate Compound 235.
  • a mixture of 2- (benzyloxy)acetaldehyde 233 (1.6 g, 10.6 mmol) and compound 234 (3.7 g, 10.6) in toluene (50 mL), was stirred at reflux overnight and then concentrated to dryness. The residue was purified by silica gel column (PE : EA 10 : 1) to give crude title compound 235, (E)-ethyl 4-(benzyloxy)but-2-enoate (0.8 g, 34% yield).
  • LC-MS LC method 1): m/z 221 (M+l) + .
  • Step 4 Synthesis of Intermediate Compound 236.
  • (E)-ethyl 4- (benzyloxy)but-2-enoate 235 800 mg, 3.6 mmol
  • LiOH 576 mg, 14.4 mmol
  • the reaction mixture was stirred at room temperature for 3 h.
  • the crude mixture was acidified by 2M HC1 TO adjust pH to 3-4 and extracted with ethyl acetate (100 mL).
  • Step 5 Synthesis of Intermediate Compound 238.
  • (E)-4- (benzyloxy)but-2-enoic acid 236 (2.5g, 13.01mmol) and triethylamine (1.45g, 14.31 mmol) in anhydrous THF (40 mL) under nitrogen at -78 °C was added trimethylacetyl chloride (1.72g, 14.3 lmmol).
  • the reaction mixture was stirred at -78 °C for 10 minutes, 0 °C for 1 hour, then re-cooled to -78°C.
  • Step 1 Synthesis of Intermediate Compound 250. To a solution compound 248 (2 g, 13.42 mmol) in 1,4-dioxane (50 mL) was added compound 249 (4.8 g, 13.42 mmol) and DIPEA (5.2 g,
  • Step 2 Synthesis of Intermediate Compound 251.
  • (R)-methyl 3-(tert- butyldiphenylsilyloxy)-2-(2-chloro pyrimidin-4-ylamino)propanoate 250 (3.5 g, 7.45 mmol) in 1,4- dioxane (60 mL)
  • PMBNH 2 (1.12 g, 8.19 mmol
  • DIPEA 2.88 g, 22.34mmol
  • Step 3 Synthesis of Intermediate Compound 252.
  • (R)-methyl 3-(tert-butyldiphenyl silyloxy)-2-(2-(4-methoxybenzylamino)pyrimidin-4-ylamino)propanoate 251 (3 g, 5.26 mmol) in the mixture of CH 3 CN (120 mL) and water (24 mL), was added CAN ( 14.41 g,
  • Step 4 Synthesis of Intermediate Compound 253.
  • (R)-methyl 2-(2- aminopyrimidin-4-ylamino)-3-(tert-butyldi phenylsilyloxy)propanoate 252 800 mg, 1.78 mmol
  • DCM DCM
  • AC 2 O 18.1.2 mg, 1.78 mmol
  • pyridine 421.3 mg, 5.33 mmol
  • the resulting mixture was stirred at 80 °C overnight.
  • the crude mixture was quenched with aq. NaHCC , extracted with ethyl acetate (50 mL). The organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated to dryness.
  • Step 5 Synthesis of Intermediate Compound 254.
  • (R)-methyl 2-(2- acetamidopyrimidin-4-ylamino)-3-(tert-butyldiphenylsilyloxy) propanoate 253 200 mg, 0.40 mmol
  • LiOH 51.15 mg, 1.22 mmol
  • the reaction mixture was stirred at room temperature for 1 h.
  • the crude mixture was acidified by 2M HC1 to adjust pH to 6.
  • the resulting mixture was extracted with ethyl acetate (20 mL).
  • Step 1 Synthesis of Intermediate Compound 259.
  • methyl(2S)-2- [[(2S,3S)-2-amino-3-hydroxy-butanoyl]amino]-3-[tert-butyl(diphenyl)silyl]oxy-propanoate 500 mg, 1.09 mmol (258) in DMF (10 mL) was added 3-bromopropanoyl chloride (280.33 mg, 1.64 mmol) dropwise at 0 °C.
  • K2CO3 452 mg, 3.27 mmol.
  • the resulting mixture was stirred at 20 °C for 10 h.
  • Step 2 Synthesis of Intermediate Compound 260.
  • LiOH H 2 0 57.2 mg, 1.40 mmol.
  • the reaction mixture was stirred at room temperature for 3 h.
  • the crude mixture was acidified by 2M HCl to adjust the pH to 3-4.
  • the resulting mixture was extracted with ethyl acetate (10 mL).
  • Step 1 Intermediate benzyl (2S,3R)-benzyl 3-(benzyloxy)-2-(N- methylsulfamoylamino)butanoate 265.
  • pyridine 793 mg, 10 mmol
  • N- methylsulfamoyl chloride 650 mg, 5 mmol
  • strains from Gram-negative pathogen Escherichia coli were streaked from frozen stocks for single colonies on tryptic soy agar plates and incubated at 37°C for 18 - 24 hours. From these plates, up to 10 individual colonies were resuspended in sterile saline or Mueller Hinton II broth (MHB-II) or 3 - 5 colonies were inoculated into 3 mL MHB-II broth and grown at 37°C until sufficiently turbid. Either of these suspensions was used as the starting inoculum after adjustment to 2 - 8 x 10 5 CFU/mL in the assay.
  • Compounds were prepared by making a stock solution at -100-1000 times the highest concentration to be assayed. This stock solution was used to make two-fold serial dilutions in water or MHB-II in sterile, polystyrene 96 well microtiter assay plates for a total volume (including the bacterial inoculum) of 100 uL. Plates were incubated at 35-37°C for 16 - 20 hours and the MIC was defined as the lowest concentration of compound that completely inhibited visible growth.
  • Table I shows the intrinsic MIC of the example compounds, as well as the potentiation activity as a function of the MIC of rifampicin and 8 ⁇ g/mL of potentiator.
  • Intrinsic MIC with 8 ⁇ g/mL of Intrinsic MIC rifampicin* with
  • Intrinsic MIC with 8 ⁇ g/mL of Intrinsic MIC rifampicin* with

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Abstract

L'invention concerne des composés représentés par la formule (I) ou un tautomère de ceux-ci, ou un sel pharmaceutiquement acceptable de l'un ou l'autre des composés mentionnés. Les variables A, R1 et R2 sont définies dans la description. L'invention concerne en outre des compositions pharmaceutiques comprenant un composé représenté par la formule I, conjointement avec au moins un excipient pharmaceutiquement acceptable. L'invention concerne également un procédé de sensibilisation de bactéries à un agent antibactérien, qui consiste à administrer à un patient infecté par les bactéries, simultanément ou séquentiellement, une quantité thérapeutiquement efficace de l'agent antibactérien et un composé représenté par la formule (I).
PCT/US2017/029879 2016-04-27 2017-04-27 Analogues de la polymyxine utiles en tant que potentialisateurs d'antibiotique Ceased WO2017189866A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020014501A1 (fr) * 2018-07-11 2020-01-16 Cidara Therapeutics, Inc. Compositions et procédés pour le traitement d'infections bactériennes
WO2022232245A3 (fr) * 2021-04-27 2022-12-15 The Rockefeller University Macolacines et leurs procédés d'utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017734A1 (fr) * 2006-08-11 2008-02-14 Northern Antibiotics Oy Dérivés de polymyxine et leurs utilisations
WO2009098357A1 (fr) * 2008-02-08 2009-08-13 Northern Antibiotics Oy Dérivés de polymyxine à queue acide gras court et leurs utilisations
WO2016100578A2 (fr) * 2014-12-16 2016-06-23 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes

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Publication number Priority date Publication date Assignee Title
WO2008017734A1 (fr) * 2006-08-11 2008-02-14 Northern Antibiotics Oy Dérivés de polymyxine et leurs utilisations
WO2009098357A1 (fr) * 2008-02-08 2009-08-13 Northern Antibiotics Oy Dérivés de polymyxine à queue acide gras court et leurs utilisations
WO2016100578A2 (fr) * 2014-12-16 2016-06-23 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes

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"Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH
G. STEFFEN PAULEKUHN ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, 2007, pages 6665
SYNTHESIS, vol. 47, 2015, pages 2088 - 2092
VAARA M ET AL: "Structure-activity studies on novel polymyxin derivatives that carry only three positive charges", PEPTIDES, ELSEVIER, AMSTERDAM, NL, vol. 31, no. 12, 1 December 2010 (2010-12-01), pages 2318 - 2321, XP027451708, ISSN: 0196-9781, [retrieved on 20100922], DOI: 10.1016/J.PEPTIDES.2010.09.010 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020014501A1 (fr) * 2018-07-11 2020-01-16 Cidara Therapeutics, Inc. Compositions et procédés pour le traitement d'infections bactériennes
WO2022232245A3 (fr) * 2021-04-27 2022-12-15 The Rockefeller University Macolacines et leurs procédés d'utilisation

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